start-ver=1.4
cd-journal=joma
no-vol=11
cd-vols=
no-issue=24
article-no=
start-page=3993
end-page=
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2022
dt-pub=20221210
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=SCAND1 Reverses Epithelial-to-Mesenchymal Transition (EMT) and Suppresses Prostate Cancer Growth and Migration
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Epithelial-mesenchymal transition (EMT) is a reversible cellular program that transiently places epithelial (E) cells into pseudo-mesenchymal (M) cell states. The malignant progression and resistance of many carcinomas depend on EMT activation, partial EMT, or hybrid E/M status in neoplastic cells. EMT is activated by tumor microenvironmental TGF beta signal and EMT-inducing transcription factors, such as ZEB1/2, in tumor cells. However, reverse EMT factors are less studied. We demonstrate that prostate epithelial transcription factor SCAND1 can reverse the cancer cell mesenchymal and hybrid E/M phenotypes to a more epithelial, less invasive status and inhibit their proliferation and migration in DU-145 prostate cancer cells. SCAND1 is a SCAN domain-containing protein and hetero-oligomerizes with SCAN-zinc finger transcription factors, such as MZF1, for accessing DNA and the transcriptional co-repression of target genes. We found that SCAND1 expression correlated with maintaining epithelial features, whereas the loss of SCAND1 was associated with mesenchymal phenotypes of tumor cells. SCAND1 and MZF1 were mutually inducible and coordinately included in chromatin with hetero-chromatin protein HP1 gamma. The overexpression of SCAND1 reversed hybrid E/M status into an epithelial phenotype with E-cadherin and beta-catenin relocation. Consistently, the co-expression analysis in TCGA PanCancer Atlas revealed that SCAND1 and MZF1 expression was negatively correlated with EMT driver genes, including CTNNB1, ZEB1, ZEB2 and TGFBRs, in prostate adenocarcinoma specimens. In addition, SCAND1 overexpression suppressed tumor cell proliferation by reducing the MAP3K-MEK-ERK signaling pathway. Of note, in a mouse tumor xenograft model, SCAND1 overexpression significantly reduced Ki-67(+) and Vimentin(+) tumor cells and inhibited migration and lymph node metastasis of prostate cancer. Kaplan-Meier analysis showed high expression of SCAND1 and MZF1 to correlate with better prognoses in pancreatic cancer and head and neck cancers, although with poorer prognosis in kidney cancer. Overall, these data suggest that SCAND1 induces expression and coordinated heterochromatin-binding of MZF1 to reverse the hybrid E/M status into an epithelial phenotype and, inhibits tumor cell proliferation, migration, and metastasis, potentially by repressing the gene expression of EMT drivers and the MAP3K-MEK-ERK signaling pathway.
en-copyright=
kn-copyright=

en-aut-name=EguchiTakanori
en-aut-sei=Eguchi
en-aut-mei=Takanori
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=CsizmadiaEva
en-aut-sei=Csizmadia
en-aut-mei=Eva
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=KawaiHotaka
en-aut-sei=Kawai
en-aut-mei=Hotaka
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=ShetaMona
en-aut-sei=Sheta
en-aut-mei=Mona
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=YoshidaKunihiro
en-aut-sei=Yoshida
en-aut-mei=Kunihiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=PrinceThomas L.
en-aut-sei=Prince
en-aut-mei=Thomas L.
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=WegielBarbara
en-aut-sei=Wegiel
en-aut-mei=Barbara
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=CalderwoodStuart K.
en-aut-sei=Calderwood
en-aut-mei=Stuart K.
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

affil-num=1
en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=2
en-affil=Division of Surgical Sciences, Department of Surgery, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School
kn-affil=

affil-num=3
en-affil=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=4
en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=5
en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=6
en-affil=Ranok Therapeutics
kn-affil=

affil-num=7
en-affil=Division of Surgical Sciences, Department of Surgery, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School
kn-affil=

affil-num=8
en-affil=Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School
kn-affil=
en-keyword=epithelial-to-mesenchymal transition (EMT)
kn-keyword=epithelial-to-mesenchymal transition (EMT)
en-keyword=hybrid E/M
kn-keyword=hybrid E/M
en-keyword=partial EMT
kn-keyword=partial EMT
en-keyword=SCAND1
kn-keyword=SCAND1
en-keyword=MZF1
kn-keyword=MZF1
en-keyword=SCAN zinc finger transcription factors
kn-keyword=SCAN zinc finger transcription factors
en-keyword=gene expression
kn-keyword=gene expression
en-keyword=cancer prognosis
kn-keyword=cancer prognosis
en-keyword=collective migration
kn-keyword=collective migration
en-keyword=metastasis
kn-keyword=metastasis
END